A. Free Radicals
Free radicals are molecules with one or more unpaired electrons in their outer orbitals. The presence of these electrons together with the tendency of molecules to seek the lowest stable energy state causes free radicals to be highly reactive and generally short lived. Among the free radicals commonly found in vivo are oxygen, the superoxide anion and the hydroxyl radical. These are typically referred to as “oxidants” and are often the result of cascades in which electrons are passed from molecule to molecule.
B. Injuries and Free Radical Damage
Injuries such as wounds and burns generate free radicals that have both local and systemic effects. Locally, free radicals have been implicated in both tissue ischemia (Granger, et al., Gastroenterology 81:22–29 (1981); Parks, et al., Gastroenterology 82:9–15 (1982)) and reperfusion injuries (Schiller, et al., Critical Care Med. 21:S92–S100 (1993)). Systemically, burns often cause dysfunction of the heart, lungs and liver. Researchers have found that burn healing is improved when lipid peroxidation (typically caused by the action of free radicals) is reduced (LaLonde, et al., J. Burns Care & Rehabilitation 17:379–383 (1996)).
C. Photodamage
Exposure of skin to electromagnetic radiation in the ultraviolet and visible portions of the spectrum and ionizing radiation may result in damage to both the proteins and the DNA in skin cells. Such “photodamage” has been correlated with the induction of non-melanoma skin cancer, immune function suppression and photoaging.
Exposure of skin to ultraviolet and ionizing radiation and the concomitant pathobiologies have been linked to the generation of oxidants as well as to a reduction in anti-oxidant levels and activity (Stewart, et al., J. Inv. Dermatol. 106:1086–1089 (1996); Darr, et al., Brit. J. Dermatol. 127:247–253 (1992)). Specifically, research has shown that there is a reduction in epidermal superoxide dysmutase activity and in the levels of vitamin C and vitamin E after exposure to UVB radiation. Elimination of oxidants (e.g., by application of exogenous anti-oxidants) or prevention of oxidant production (e.g., by reduction of exposure to ionizing radiation) can alleviate or prevent dermatological damage. The adverse effects of ionizing radiation include edema, vasodilation, lymphocytic and neutrophilic infiltration in the dermis, dyskeratotic keratinocytes and spongiosis of the epidermis.
D. Use of Anti-Oxidants to Detoxify Free Radicals
A number of different strategies have been used in attempting to prevent or reduce free radical damage. Endogenous anti-oxidants, e.g., superoxide dysmutase, catalase or glutathione peroxidase, may be used to protect cell membranes and agents such as ascorbic acid and glutathione may be used to protect cytosols. Other anti-oxidants, such as alpha-tocopherol and tretinoin, have also been used to ameliorate the effect of free radicals.
Administration of superoxide dysmutase, post-ischemia prevents the increased capillary permeability which accompanies reperfusion injuries (Granger, et al., Gastroenterology 81:22–29 (1981)) and the ablation of free radical generation prior to, and at the time of, reperfusion may prevent or lessen the severity of multiple system organ failure syndrome (Schiller, et al., Critical Care Med. 21:S92–S100 (1993)). Stewart, et al. have shown that UVB-induced DNA damage in human keratinocytes is attenuated by supplementing culture medium surrounding the cells with anti-oxidants such as vitamin C, selenite, or a water-soluble vitamin E analog (J. Inv. Dermatol. 106:1086–1089 (1996)).
E. Selegiline and Desmethylselegiline
Monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) are enzymes found in both in the central nervous system and in peripheral tissues. MAO-A and MAO-B catalyze the oxidative deamination of primary amines, including neuroactive and vasoactive amines, resulting in the formation of toxic free radical species and free radical-generating cascades. Selegiline is a potent and selective inhibitor of monoamine oxidase B and has been reported to have an action in protecting or rescuing neurons of the central nervous system (Knoll, Mount Sinai J. Med. 55:67–74 (1988)). Although the exact mechanism by which selegiline causes its effects is not known, there is evidence suggesting that it may provide neuroprotection or neuronal rescue by reducing oxidative damage caused by monoamine oxidase and/or other oxidants (Jenner, et al., Neurology 47:S162–S170 (1996)). In this regard, selegiline has been shown to increase the activity of the endogenous anti-oxidants superoxide dysmutase, catalase and glutathione peroxidase (Id.).
Desmethylselegiline, one of the metabolites of selegiline, exhibits reduced MAO-B inhibitory activity in comparison to selegiline and its activity with respect to the inhibition of MAO-A is decreased to an even greater extent. Thus, it is expected that desmethylselegiline should produce selegiline-like neuroprotective effects with a decreased risk of side effects associated with MAO-A inhibition.
Although selegiline has been used to treat Parkinson's disease, its use as a treatment for injuries, such as burns and wounds, and for alleviating dermatological damage, such as photodamage, has not been known heretofore. The present invention is directed to methods which rely upon the administration of selegiline or desmethylselegiline to speed the healing and reduce the complications associated with these conditions.